Additive manufacturing, also known as three-dimensional (3D) printing, has the potential to revolutionize the way surgeons address complicated reconstructive efforts in pathogenesis, congenital deformity, senescence, oral, maxillofacial, and/or orthopedic trauma, and cancer defect repairs, just to name a few of the many possible biomedical applications for 3D printing. While numerous 3D printing methods have been reported, photocrosslinking-based printing methods in particular have shown potential for reliable, high-fidelity rendering of solid-cured polymer scaffolds that are designed to fit defects visualized by medical imaging. Advances in image projection via digital light printing (DLP) technology have enabled the 3D printing of tissue engineering scaffolds with complex geometric designs coupled with very fine (<50 μm) features.
To realize this potential, efforts have been made to develop a cost effective, non-toxic, biodegradable polymer that works well with known 3D printing technologies, including photochemical cross linking techniques. Moreover, since the idea is for these 3D printed structures to be implanted into the human body, the polymers used must withstand regulatory scrutiny. While there are many inert photocrosslinkable resins, very few are non-toxic, implantable and resorbable. Of this final category the most explored are polylactides, poly(c-caprolactone), and poly(propylene fumarate) (PPF). In regards to resorption profiles, polylactides have occasionally been found to undergo rapid bulk degradation leading to a localized acidosis and inflammation. Poly(ε-caprolactone) is known to degrade very slowly, sometimes over years, thereby limiting the necessary remodeling or vascularization of neotissues. Poly(propylene fumarate) (PPF) was developed, in part, because of a desire to have a material which has safe and controllable degradation and properties expected to be useful for such things as controlled drug release, stents, blood vessels, nerve grafts, and cartilage tissue engineering, especially bone tissue engineering. Since its invention via the step growth polymerization method more than two decades ago, PPF has been investigated with much success as scaffolding materials for skeletal repair. Subsequent reports have improved upon the synthetic methods and resulting materials.
One major factor limiting the availability of resorbable photo-cross linkable polymers such as PPF is the lack of GMP-grade materials, i.e., materials which meet Good Manufacturing Practices requirements implemented by the FDA, required to push forward into large animal models and pilot human trials. PPF is traditionally synthesized using one of a variety of step-growth condensation reactions. To date, it has not been possible to reliably and reproducibly synthesize well-defined, low-molecular-mass oligomers on the scale required for widespread 3D printing applications and commercialization. In particular, known step-growth methods of synthesizing PPF require high energy (heat) input, high vacuum, long reaction times, and result in low conversion (˜35%) with uncontrolled molecular mass distribution, conjugate-addition side reactions, and unwanted cross-linking, all of which greatly influence the mechanical properties and degradation rates of the final product. Moreover, these methods are slow, labor intensive and very expensive, and, as a result, have not been found commercially viable.
Particularly problematic is the difficulty in controlling the molecular mass distribution inherent in these step-growth methods. No two batches are exactly the same. These polymers tend to have a relatively high molecular mass distribution (m) (also known as the Polydispersity Index (PDI)), and the colors and mechanical/viscosity properties of the polymers are inconsistent from batch to batch. This batch to batch variation has been found to lead to significant difficulty in predicting mechanical properties that influence biological performance, such as the resorption time, the evenness of resorption (due to long chains acting as a nexus in some locations and not others—i.e., uneven cross linking mesh), as well as uneven cross linking incorporation of other resins used as a solvent(s), photo-initiator(s), dye(s), pigment(s), or component(s) (e.g., diethyl fumarate (DEF), bioactive molecules) during 3D printing. The inability of researchers to reliably predict the 3D printing and subsequent biological performance of these polymers has made it very difficult to obtain the necessary regulatory approvals for use of these polymers in implants and other medical devices. In fact, it is believed that to date PPF has not been part of any FDA-approved device or therapy, despite more than two decades of continuous study of its use in regenerative medicine and successful experimental results.
More recently, PPF with a high molecular mass, a narrow m (below 1.6) and low ether linkage (<1%) have been successfully synthesized using a chain growth mechanism with mild reaction conditions. In this method, maleate anhydride and epoxide are polymerized through a ring-opening copolymerization with chromium salen as a catalyst at 45° C., and the produced poly(propylene maleate) (PPM) is then isomerized using diethylamine at room temperature for 16 hours to yield PPF. The PPF synthesized in this way was a solid and had a MW of more than 4 kDa, a molecular mass distribution of 1.6 and less than 1% ether linkage with 99% conversion. Compared with traditional synthesis methods, the chain growth mechanism provides PPF with better molecular properties and the reaction is more reproducible, making it possible to produce PPF with controlled properties for further mechanical, toxicity and degradation tests, and for large-scale production in manufacturing. Unfortunately, however, the high molecular weights, lack of flowability, and residual chromium metal of the PPF polymers made using these methods, render them unsuitable for 3D printing or other applications in regenerative medicine.
What is needed in the art is a low molecular weight, flowable, non-toxic, resorbable PPF polymer with constrained and predictable material properties and related methods for its making and use, which are suitable for 3D printing and use in medical devices and can be made inexpensively and in commercially reasonable quantities using GMP.